Process for preparing acyclic HCV protease inhibitors

ABSTRACT

Disclosed are highly convergent processes for preparing compounds of formula (I), which compounds are potent active agents for the treatment of hepatitis C virus (HCV) infection:  
                 
 
     The disclosed processes use S N Ar-type coupling reactions between peptidic compounds having a hydroxyproline moiety of the following formula:  
                 
and halogenated or sulfonated bromoquinoline compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the following U.S. ProvisionalApplications: 60/574,182, filed May 25, 2004; 60/652,018, filed Feb. 11,2005 and 60/660,745, filed Mar. 11, 2005.

BACKGROUND OF THE INVENTION

1. Technical Field

The invention relates to an improved process for the preparation ofacyclic compounds useful as agents for the treatment of hepatitis Cviral (HCV) infections.

2. Background Information

The compounds of the following formula (I) and methods for theirpreparation are disclosed in the following patent publications: WO00/09543; U.S. Pat. No. 6,323,180 B1; and U.S. Patent ApplicationPublication No. 2005/0020503 A1:

wherein Het is a five-, six- or seven-membered saturated or unsaturatedheterocycle containing from one to four heteroatoms selected fromnitrogen, oxygen and sulfur; said heterocycle being substituted with R¹at any available position on the heterocycle;

-   R¹ is R²⁰, —NR²²COR²⁰, —NR²²COOR²⁰—NR²²R²¹ and —NR²²CONR²¹R²³,    wherein R²⁰ is selected from (C₁₋₈)alkyl, (C₃₋₇)cycloalkyl and    (C₃₋₇)cycloalkyl(C₁₋₄)alkyl-, wherein said cycloalkyl or    cycloalkylalkyl may be mono-, di- or tri-substituted with    (C₁₋₃)alkyl;-   R²¹ is H or has one of the meanings of R²⁰ as defined above,-   R²² and R²³ are independently selected from H and methyl,-   Alk is a C₁-C₆ alkyl group;-   A is O or NH;-   B is (C₁₋₁₀)alkyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₄)alkyl,    -   a) wherein said cycloalkyl, cycloalkylalkyl may be mono-, di- or        tri-substituted with (C₁₋₃)alkyl; and    -   b) wherein said alkyl, cycloalkyl, cycloalkylalkyl may be mono-        or di-substituted with substituents selected from hydroxy and        (C₁₋₄)alkoxy; and    -   c) wherein all said alkyl-groups may be mono-, di- or        tri-substituted with halogen; and    -   d) wherein said cycloalkyl-groups being 4-, 5-, 6- or 7-membered        having optionally one (for the 4-, 5, 6, or 7-membered) or two        (for the 5-, 6- or 7-membered) —CH₂-groups not directly linked        to each other replaced by —O— such that the O-atom is linked to        the group A via at least two C-atoms;-   R² is (C₁₋₈)alkyl, (C₃₋₇)cycloalkyl or (C₃₋₇)cycloalkyl(C₁₋₃)alkyl,    wherein said cycloalkyl groups may be mono-, di- or tri-substituted    with (C₁₋₄)alkyl;-   R³ is ethyl or vinyl;-   R^(C) is hydroxyl, C₁-C₆ alkoxy or NHSO₂R^(S) wherein R^(S) is    (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₆)alkyl, phenyl,    naphthyl, pyridinyl, phenyl(C₁₋₄)alkyl, naphthyl(C₁₋₄)alkyl or    pyridinyl(C₁₋₄)alkyl; all of which optionally being mono-, di- or    tri-substituted with substituents selected from halogen, hydroxy,    cyano, (C₁₋₄)alkyl, (C₁₋₆)alkoxy, —CO—NH₂, —CO—NH(C₁₋₄-alkyl),    —CO—N(C₄-alkyl)₂, —NH₂, —NH(C₁₋₄-alkyl) and —N(C₁₋₄-alkyl)₂; and all    of which optionally being monosubstituted with nitro;    -   or R^(S) can be further selected from: —NH(C₁₋₆alkyl),        N(C₁₋₆alkyl)₂, -Het,        or a pharmaceutically acceptable salt or ester thereof.

The compounds of formula (I) are disclosed in the above-mentioned patentdocuments as being active agents for the treatment of hepatitis C virus(HCV) infections. The methods disclosed for the preparation of thesecompounds included many synthetic steps and were extremely linear, inthat groups were built up sequentially in small increments, rather thansynthesizing large fragments and bringing them together (convergency).The problem addressed by the present invention is to provide highlyconvergent processes which allow for the manufacture of these compoundswith a minimum number of steps and with sufficient overall yield.

BRIEF SUMMARY OF THE INVENTION

The processes provided by the present invention, as described herein,are highly convergent and this convergency manifests itself in a muchshorter synthetic sequence leading to the compounds of Formula (I). TheS_(N)Ar assembly strategy of the present invention utilizingmonopeptides, dipeptides and tripeptides eliminates steps from the knownsynthetic sequence since it is not necessary to invert the naturalhydroxyproline stereochemistry. This allows one to utilize the far lessexpensive natural aminoacid as starting material, thereby gaining afurther economic advantage.

The processes of the present invention also provide for the preparationof certain intermediates in crystalline form. This crystallinity impartsnumerous large scale handling and storage advantages over an amorphoussolid or an oil.

The processes of the present invention all provide for the preparationof Formula (I) via S_(N)Ar coupling reaction between a compound having ahydroxyproline moiety of the following general formula A:

and the following quinoline compound QUIN:

wherein Het and R¹ are as defined previously and X is a halogen atom oran SO₂R group, wherein R is C₁₋₆alkyl, C₆ or C₁₀ aryl or heteroaryl,leading to compounds of the following general formula B:

Depending upon the hydroxyproline compound of general formula A that isused in this step, be it a mono-, di- or tripeptide, highly convergentprocesses leading to compound of Formula (I) are possible by employingstandard peptide coupling techniques as described in the schemes setforth herein.

The present invention is therefore directed to a multi-step syntheticprocess for preparing compounds of formula (I) using the syntheticsequences as described herein; particular individual steps of thismulti-step process; and particular individual intermediates used in thismulti-step process.

The present invention is also directed to novel crystalline forms ofparticular intermediates and also of the compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Definition of Terms and Conventions Used

Terms not specifically defined herein should be given the meanings thatwould be given to them by one of skill in the art in light of thedisclosure and the context. As used in the specification, however,unless specified to the contrary, the following terms have the meaningindicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbonatoms is often specified preceding the group, for example, (C₁₋₈)alkylmeans an alkyl group or radical having 1 to 8 carbon atoms and(C₃₋₇)cycloalkyl means a cycloalkyl group having from 3 to 7 carbonatoms in the ring. In general, for groups comprising two or moresubgroups, the last named group is the radical attachment point, forexample, “cycloalkylalkyl” means a monovalent radical of the formulacycloalkyl-alkyl- and phenylalkyl means a monovalent radical of theformula phenyl-alkyl-. Unless otherwise specified below, conventionaldefinitions of terms control and conventional stable atom valences arepresumed and achieved in all formulas and groups.

The term “alkyl” as used herein, either alone or in combination withanother substituent, means acyclic, straight or branched chain alkylsubstituents containing the specified number of carbon atoms.

The term “alkoxy” as used herein, either alone or in combination withanother substituent, means an alkyl group as defined above linked as asubstituent through an oxygen atom: alkyl-O—.

The term “C₆ or C₁₀ aryl” as used herein, either alone or in combinationwith another substituent, means either an aromatic monocyclic systemcontaining 6 carbon atoms or an aromatic bicyclic system containing 10carbon atoms. For example, aryl includes a phenyl or a naphthyl ringsystem.

The term “Het” as used herein, either alone or in combination withanother substituent, means a monovalent substituent derived by removalof a hydrogen from a five-, six-, or seven-membered saturated orunsaturated (including aromatic) heterocycle containing carbon atoms andfrom one to four ring heteroatoms selected from nitrogen, oxygen andsulfur. Examples of suitable heterocycles include: tetrahydrofuran,thiophene, diazepine, isoxazole, piperidine, dioxane, morpholine,pyrimidine or

The term “Het” also includes a heterocycle as defined above fused to oneor more other cycle be it a heterocycle or a carbocycle, each of whichmay be saturated or unsaturated. One such example includesthiazolo[4,5-b]-pyridine. Although generally covered under the term“Het”, the term “heteroaryl” as used herein precisely defines anunsaturated heterocycle for which the double bonds form an aromaticsystem. Suitable example of heteroaromatic system include: quinoline,indole, pyridine,

In general, all tautomeric forms and isomeric forms and mixtures,whether individual geometric isomers or optical isomers or racemic ornon-racemic mixtures of isomers, of a chemical structure or compound areintended, unless the specific stereochemistry or isomeric form isspecifically indicated in the compound name or structure.

The term “pharmaceutically acceptable salt” as used herein includesthose derived from pharmaceutically acceptable bases. Examples ofsuitable bases include choline, ethanolamine and ethylenediamine. Na⁺,K⁺, and Ca⁺⁺ salts are also contemplated to be within the scope of theinvention (also see Pharmaceutical Salts, Birge, S. M. et al., J. Pharm.Sci., (1977), 66, 1-19, incorporated herein by reference).

The term “pharmaceutically acceptable ester” as used herein, eitheralone or in combination with another substituent, means esters of thecompound of formula I in which any of the carboxyl functions of themolecule, but preferably the carboxy terminus, is replaced by analkoxycarbonyl function:

in which the R moiety of the ester is selected from alkyl (e.g. methyl,ethyl, n-propyl, t-butyl, n-butyl); alkoxyalkyl (e.g. methoxymethyl);alkoxyacyl (e.g. acetoxymethyl); aralkyl (e.g. benzyl); aryloxyalkyl(e.g. phenoxymethyl); aryl (e.g. phenyl), optionally substituted withhalogen, C₁₋₄ alkyl or C₁₋₄ alkoxy. Other suitable prodrug esters arefound in Design of Prodrugs, Bundgaard, H. Ed. Elsevier (1985)incorporated herewith by reference. Such pharmaceutically acceptableesters are usually hydrolyzed in vivo when injected in a mammal andtransformed into the acid form of the compound of formula I. With regardto the esters described above, unless otherwise specified, any alkylmoiety present advantageously contains 1 to 16 carbon atoms,particularly 1 to 6 carbon atoms. Any aryl moiety present in such estersadvantageously comprises a phenyl group. In particular the esters may bea C₁₋₁₆ alkyl ester, an unsubstituted benzyl ester or a benzyl estersubstituted with at least one halogen, C₁₋₆ alkyl, C₁₋₆ alkoxy, nitro ortrifluoromethyl.

The following chemicals may be referred to by these abbreviations:Abbreviation Chemical Name ACN Acetonitrile BOC Tert-butoxylcarbonylDABCO 1,4-diazabicyclo[2.2.2]octane DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCC 1,3-Dicyclohexylcarbodiimide DCHADicyclohexylamine DCM Dichloromethane DIPEA or Diisopropylethylamine orHünigs-Base DIEA DMAP Dimethylaminopyridine DMF N,N-DimethylformamideDMSO Dimethylsulfoxide DMTMM 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium Chloride EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiinide hydrocholide HATU O-(7-azabenzotriazol-1-yl)-N,N,′,N′-tetramethyluronium hexafluorophosphate HBTUO-Benzotriazol-1-yl-N,N,′,N′- tetramethyluronium hexafluorophosphateHOAT 1-Hydroxy-7-azabenzotriazole HOBT 1-Hydroxybenzotriazole IPAIsopropyl alcohol KDMO Potassium 3,7-dimethyl-3-octanoxide MCHMethylcyclohexane MIBK 4-Methyl-2-pentanone MTBE Methyl, tert-butylether NMP 1-Methyl-2-pyrrolidinone SEH Sodium 2-ethylhexanoate TBTUO-(Benzotriazol-1-yl)-N,N,N′,N′- tetramethyluronium tetrafluoroborateTHF Tetrahydofuran

EMBODIMENTS OF THE INVENTION

In the synthetic schemes below, unless specified otherwise, all thesubstituent groups in the chemical formulas shall have the same meaningsas in the Formula (I). The reactants used in the synthetic schemesdescribed below may be obtained either as described herein, or if notdescribed herein, are themselves either commercially available or may beprepared from commercially available materials by methods known in theart. Certain starting materials, for example, may be obtained by methodsdescribed in the International Patent Applications WO 00/09543, WO00/09558, WO 00/59929, U.S. Pat. No. 6,323,180 B1 and U.S. Pat. No.6,608,027 B1.

Optimum reaction conditions and reaction times may vary depending on theparticular reactants used. Unless otherwise specified, solvents,temperatures, pressures, and other reaction conditions may be readilyselected by one of ordinary skill in the art. Specific procedures areprovided in the Synthetic Examples section. Typically, reaction progressmay be monitored by High Pressure Liquid Chromatography (HPLC), ifdesired, and intermediates and products may be purified bychromatography on silica gel and/or by recrystallization.

I. Preparation of QUIN

In one embodiment, the present invention is directed to the followinggeneral multi-step synthetic methods for preparing the intermediatecompounds of formula QUIN, as well as the individual steps andintermediates set forth therein. Those compounds of formula QUIN whereinX is a halogen are herein designated as formula QUIN-1 and thosecompounds of formula QUIN wherein X is an SO₂R group, where R is asdefined previously, are herein designated as formula QUIN-2. Thecompounds of formula QUIN-1 and QUIN-2 are prepared as set forth inSchemes IA and IB below, respectively:

wherein each Alk is independently a C₁-C₆ alkyl group, X is a halogenatom, Z is tert-butyl or t-butyl-oxy, and R¹ and Het in this andsubsequent schemes are as defined for Formula I.

In the first step, a compound of formula 1 is treated with a base and abrominating agent to obtain compound 2. The general requirements forthis step are the use of a base of strength sufficient to form thedesired dianion. This could be any alkyllithium, a metalloamide such asLithium diisopropylamide (LDA), Lithium tetramethylpiperidide, ametallohexamethyldisilazide such as KHMDS, an organozincate, a metalalkoxide in a cation-solvating solvent such as DMSO, and the like. Thepreferred bases would be n-Butyllithium and LDA. Any organic solventthat does not interfere with the dianion formation could be used, suchas THF, alkyl-THF's, dioxane, alkanes, cycloalkanes, dialkylethers suchas MTBE, cyclopentylmethylether, dibutylether, and the like. Thepreferred solvents would be THF, alkyl-THF's and alkanes. Thetemperature for the dianion formation could be between −100° C. and 25°C., with the preferred range between −30° C. and 25° C. The brominatingreagent could be any compound which contains a labile bromine atom suchas Br₂, NBS, bromohydantoins, N-bromophthalimides, bromohaloalkanes suchas 1,2-dibromotetrachloroethane and perfluoroalkylbromides, and thelike. The preferred brominating reagents would be the bromohaloalkanes.Once the dianion has been generated in a suitable solvent, thebrominating reagent could be added neat or in solution, or alternativelythe dianion could be added to the brominating reagent either neat or insolution. The preferred mode would be to add the dianion slowly to thebrominating reagent in solution. The temperature for the brominationcould be between −100° C. and 25° C., with the preferred range between−30° C. and 25° C.

In the next step, compound 2 is hydrolyzed by treatment with an aqueousacid mixture to obtain 3. Any aqueous acid mixture could be used such aswater with [trifluoroacetic acid, a chloroacetic acid such astrichloroacetic acid, a sulfonic acid such as methanesulfonic acid,hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, a strongacid resin such as DOWEX 50], and the like. The preferred acids would behydrochloric acid and sulfuric acid in 2-12 M concentration, preferablyat least 6M. Cosolvents that are miscible with water could also be used,such as alcohols like ethanol, isopropanol, or ethers such as DME,diglyme, and the like. The hydrolysis could be carried out between 0° C.and 200° C., with the preferred temperature between 0° C. and 100° C.

In the next step, compound 3 is treated with an alkylated nitrile(Alk-CN) and a Lewis acid to obtain compound 4. For the conversion of 3to 4, Lewis acids by themselves or in combination, could be used, suchas AlCl₃, BCl₃, GaCl₃, FeCl₃ and mixtures thereof, and the like. Thepreferred method would be to use BCl₃ with AlCl₃. Any solvent which willnot be easily acylated could be used such as halocarbons, halobenzenes,alkylbenzenes such as toluene, and alkylnitriles such as acetonitrile,with the preferred solvents being 1,2-dichloroethane, fluorobenzene,chlorobenzene and toluene. The reaction temperature could be between 0°C. and 150° C., preferably between 25° C. and 75° C.

In the next step, compound 4 is acylated with compound 5 to obtaincompound 6. For the conversion of 4 to 6, acylation could be achieved byeither first converting carboxylic acid 5 to an activated form such asan acid chloride or by using standard peptide coupling protocols. Thepreferred method would be to create the acid chloride of compound 5using oxalyl chloride or thionyl chloride. This activated species wouldthen be coupled with aniline 4 in any organic solvent or in water, withor without an added base. The preferred solvents would be NMP and THFand the preferred base (if used) is triethylamine. The reactiontemperature could be between −30° C. and 150° C., preferably between−20° C. and 50° C.

In the next step, compound 6 is cyclized in the presence of a base toobtain compound 7. Compound 6 can be isolated and purified, oralternatively, crude 6 in an organic solvent such as NMP can simply besubjected to the cyclization conditions to furnish quinolone 7 directly,preforming two steps in a one-pot process. For the conversion of 6 to 7in Scheme I, any base capable of forming the enolate could be used, suchas t-BuOK, KDMO, LDA, and the like, with t-BuOK and KDMO beingpreferred. Any organic solvent which does not react with the enolatecould be used, such as THF's, dioxane, DMSO, NMP, DME, and the like,with NMP, DME and DMSO being preferred. The cyclization could beperformed at any temperature between 25° C. and 150° C., with 50° C. to100° C. being preferred.

In the final step, hydroxoquinoline compound 7 is treated with ahalogenating agent to obtain the compound QUIN. For the conversion of 7to QUIN in Scheme I, many halogenating reagents could be used, such asmethanesulfonyl chloride, SOCl₂, POCl₃, PCl₃, PCl₅, POBr₃, HF, and thelike, with POCl₃ and SOCl₂ being preferred. The halogenation could beperformed neat in the halogenating reagent, or in any organic solventwhich does not react with the halogenating reagent, such as DME,diglyme, THF's, halocarbons and the like, with DME and THF's beingpreferred. The reaction temperature could be between −20° C. and 150° C.with 25° C. to 100° C. being preferred.

In a first embodiment, the hydroxyl-susbtituted quinolines 7 can firstbe converted to the halogen substituted quinolines QUIN-1 according thefinal step of Scheme IA above. The compound of formula QUIN-1 is thenconverted to the target sulfonequinoline QUIN-2 by reaction with asulfinate salt RSO₂M, wherein R is as defined previously and M is analkali metal, such as PhSO₂Na, PhSO₂K or PhSO₂Cs.

Alternatively, compound 7 can be converted to the sulfonequinolineQUIN-2 in a one-pot procedure by first generating an intermediatesulfonate by reaction with an arene sulfonylchloride compound R_(A)SO₂Clwherein R_(A) is an electron rich arene group, such as benzenesulfonylchloride or tosyl chloride, in the presence of a suitable base in asutiable solvent. Suitable bases for this step include tertiary aminebases such as N-methylpyrrolidine and diisopropylethylamine, andsuitable solvents include aprotic solvents such as acetonitrile, THF,toluene and DMF, preferably acetonitrile. The resulting species is thenreacted in situ, under acidic conditions (for example in the presence ofacetic, trifluoroacetic, hydrochloric acid or the like, preferablyacetic acid), with a sulfinate salt RSO₂M wherein M is an alkali metal,,such as PhSO₂Na, PhSO₂K or PhSO₂Cs at a suitable reaction temperature,for example in the range of 0 to 100° C., preferably 25 to 50° C. Thesulfonequinoline product can be isolated from the reaction mixture usingconventional techniques well know to those skilled in the art. In oneembodiment, the sulfonequinoline can be crystallized out by cooling thesolution to room temperature and adding water. The crystallized productcan then be filtered, rinsed and washed using conventional techniques.

In particular, the individual intermediate compounds 4, 6, 7, QUIN-1 andQUIN-2, as well as the synthetic procedures to obtain these compounds,all as depicted in the above schemes, are additional aspects andembodiments of the present invention.

I.A. General Embodiment Relating to Quinoline Compounds 7, QUIN-1 andQUIN-2

Another aspect of the present invention are the quinoline intermediates7, QUIN-1 and QUIN-2 set forth above, as represented by the generalformula QUIN′ below:

wherein Het is a five-, six- or seven-membered saturated or unsaturatedheterocycle containing from one to four heteroatoms selected fromnitrogen, oxygen and sulfur; said heterocycle being substituted with R¹at any available position on the heterocycle;

-   R¹ is R²⁰, —NR²²COR²⁰, —NR²²COOR²⁰—NR²²R²¹ and —NR²²CONR²¹R²³,    wherein-   R²⁰ is selected from (C₁₋₈)alkyl, (C₃₋₇)cycloalkyl and    (C₃₋₇)cycloalkyl(C₁₋₄)alkyl-, wherein said cycloalkyl or    cycloalkylalkyl may be mono-, di- or tri-substituted with    (C₁₋₃)alkyl;-   R²¹ is H or has one of the meanings of R²⁰ as defined above,-   R²² and R²³ are independently selected from H and methyl,-   Alk is a C₁-C₆ alkyl group;-   and X′ is a hydroxyl group, a halogen atom or an SO₂R group, wherein    R is C₁₋₆alkyl, C₆ or C₁₀ aryl or heteroaryl.

With respect to the processes for preparing such QUIN′ compounds setforth previously, additional embodiments of the present inventioninclude processes comprising:

-   (a) when X′ is a hydroxyl group, cyclizing a compound of formula 6    in the presence of a sutiable base in a suitable solvent to obtain a    compound of formula 7:-   (b) when X′ is a halogen atom, treating a compound of formula 7 with    a halogenating agent to obtain a compound of formula QUIN-1:    or-   (c) when X∝ is an SO₂R group, R is C₁₋₆alkyl, C₆ or C₁₀ aryl or    heteroaryl, either: (1) treating a compound of formula 7 with a    halogenating agent to obtain a compound of formula QUIN-1 and then    reacting compound QUIN-1 with a sulfinate salt RSO₂M, where R is as    defined previously and M is an alkali metal, to obtain a compound of    formula QUIN-2; or (2) reacting a compound of formula 7 with a    compound R_(A)SO₂Cl wherein R_(A) is an electron rich arene group,    in the presence of a suitable base, and then reacting the resulting    compound in situ, under acidic conditions, with a sulfinate salt    RSO₂M, where R is as defined previously, wherein M is an alkali    metal, to obtain a compound of formula QUIN-2:    all of which processes are as set forth previously in Schemes IA and    IB above.    II. Preparation of Mono- and Di-Peptide QUIN Compounds

In additional embodiments, the present invention is directed to thesynthetic methods for preparing of the mono- and di-peptide QUINcompounds P2-QUIN, P3-P2-QUIN and P2-QUIN-P1, as outlined in Schemes IIthrough VI, as well as the individual steps and intermediates in thesemethods.

For the formation of P2-QUIN-PG in Scheme II, the S_(N)Ar reactionbetween QUIN and P2-PG, wherein PG is an amino-protecting group, couldbe performed in any organic solvent, or organic solvent mixture, thatwill not react with the base used, such as DMSO, DMF, DMA, THF, NMP,DMPU, DME, and the like, or mixtures thereof, with DMSO, DMF, and thecombination of DMF and THF being preferred. The reaction could beperformed at a temperature between −20° C. and 150° C. with 0° C. to 25°C. being preferred. Any base capable of forming the alkoxide could beused such as t-BuOK, LDA, KHMDS, KDMO, LiTMP, Cs-t-amylate and the like,with t-BuOK, Cs-t-amylate, and KDMO being preferred, and KDMO being mostpreferred. The preferred amount of base used is 3 to 6 equivalents.Cosolvents such as alkanes and cycloalkanes could also be used, withheptane being a preferred co-solvent.

In the next step, the compound P2-QUIN-PG is deprotected to obtainP2-QUIN under suitable deprotection conditions. For the formation ofP2-QUIN, any acid could be used for the removal of PG=BOC, such as TFA,HCl, methanesulfonic acid and the like, with HCl being preferred. ForPG=CBZ, any hydrogenative or transfer hydrogenative removal could beused, such as H₂ with Pd/C, NH₄HCO₃ with Pd/C, or HCO₂H with Pd/C, withHCO₂H with Pd/C being preferred. For PG=FMOC, and organic amine could beused such as Et₂NH, morpholine, piperidine, and the like, withmorpholine and piperidine being preferred. The product P2-QUIN may beisolated by precipitation from aqueous acid or by standard extractiveisolation once the free carboxylic acid has been generated.

For the formation of P3-P2-QUIN in Scheme III, the S_(N)Ar reactioncould be performed in any organic solvent, or organic solvent mixture,that will not react with the base used, such as DMSO, DMF, DMA, THF,NMP, DMPU, DME, and the like, or mixtures thereof, with DMSO, DMF, andthe combination of DMF and THF being preferred. The reaction could beperformed at a temperature between −20° C. and 150° C. with 0° C. to 25°C. being preferred. Any base capable of forming the alkoxide could beused such as t-BuOK, LDA, KHMDS, KDMO, LiTMP, Cs-t-amylate and the like,with t-BuOK, Cs-t-amylate and KDMO being preferred, and KDMO being mostpreferred. The preferred amount of base used is 3-6 equivalents.Cosolvents such as alkanes and cycloalkanes could also be used, withheptane being a preferred co-solvent.

For the formation of P2-QUIN-P1-PG in Scheme IV, the S_(N)Ar reactionbetween QUIN and P2-P1-PG, wherein PG is an amino-protecting group,could be performed in any organic solvent, or organic solvent mixture,that will not react with the base used, such as DMSO, DMF, DMA, THF,NMP, DMPU, DME, and the like, or mixtures thereof, with DMSO, DMF andthe combination of DMF and THF being preferred. The reaction could beperformed at a temperature between −20° C. and 150° C. with 0° C. to 25°C. being preferred. Any base capable of forming the alkoxide could beused such as t-BuOK, LDA, KHMDS, KDMO, LiTMP, Cs-t-amylate and the like,with t-BuOK, Cs-t-amylate and KDMO being preferred, and KDMO being mostpreferred. The preferred amount of base used is 3-6 equivalents.Cosolvents such as alkanes and cycloalkanes could also be used, withheptane being a preferred co-solvent.

The removal of the amino-protecting group in the next step to obtainP2-QUIN-P1 is performed under suitable deprotection conditions, forexample, treatment with any acid for the removal of PG=BOC, such as TFA,HCl, methanesulfonic acid and the like, with HCl being preferred. ForPG=CBZ, any hydrogenative or transfer hydrogenative removal could beused, such as H₂ with Pd/C, NH₄HCO₃ with Pd/C, or HCO₂H with Pd/C, withHCO₂H with Pd/C being preferred, with the proviso that R³ not equal tovinyl for the use of PG=CBZ. For PG=FMOC, and organic amine could beused such as Et₂NH, morpholine, piperidine, and the like, withmorpholine and piperidine being preferred.

The peptide coupling between P2-QUIN-Me (obtainable via Scheme II butusing the methyl-ester of P2-PG as starting material)_and P3 to giveP3-P2-QUIN-Me in Scheme V could be performed using any of theconventional peptide coupling reagents and protocols know in the art.Examples of suitable peptide coupling reagents include, but would not belimited to, DCC, EDC, TBTU, HATU, PYBOP, mixed anhydrides, andacidhalides. The preferred reagent would be EDC or mixed anhydridesformed with chloroformates such as isobutylchloroformate or sulfonylchlorides such as tosylchloride and a tertiary amine such asN-methylpyrrolidine or N-methylmorpholine. The coupling can be performedin any suitable non-reactive organic solvent such as, for example,acetonitrile, THF, CH₂Cl₂, 1,2-dichloroethane, DMA, NMP, DMPU ordioxane. The reaction temperature could be between −78° C. and 100° C.,with −30° C. to 25° C. being preferred.

The subsequent hydrolysis to give P3-P2-QUIN in Scheme V could beperformed with an aqueous basic solution, optionally containing aco-solvent that is miscible with H₂O such as THF, dioxane, alcohols, orDME or combinations of these co-solvents. The preferred solvent mixturewould be aqueous base containing THF as a co-solvent. Any water solublebase could be used such as LiOH, NaOH, KOH, Na₂CO₃, K₂CO₃, and the like.The preferred base would be LiOH. The amount of base could vary from 1to 100 equivalents with 1-10 equivalents being preferred. Theconcentration of base could range from 0.25 M to 12 M, with 1-4 M beingpreferred. The reaction temperature could vary from −40° C. to 100° C.,with −20° C. to 50° C. being preferred.

The peptide coupling between P2-QUIN-PG, wherein PG is anamino-protecting group, and P1 to give P2-QUIN-P1-PG in Scheme VI couldbe performed using any of the conventional peptide coupling reagents andprotocols known in the art. Examples of suitable reagents and conditionsare outlined above with respect to peptide coupling step of Scheme V.

The removal of the amino-protecting group in the last step of Scheme VIcould be performed under the conditions as described above for thedeprotection step in Scheme IV.

III. Preparation of Formula I

In additional embodiments, the present invention is directed to thesynthetic methods for preparing of the compounds of Formula I, asoutlined in Schemes VI through VIII, as well as the individual steps andintermediates in these methods.

and when R^(C) is a C₁-C₆ alkoxy group, optionally subjecting thecompound of formula (I) to de-protection conditions to obtain a compoundof formula (I) wherein R^(C) is a hydroxyl group;and when R^(C) is a hydroxyl group in the resulting compound of formula(I), optionally coupling this compound with a sulfonamide of formulaR^(S)SO₂NH₂ in the presence of a suitable coupling agent, such ascarbodiimide reagents, TBTU or HATU, to obtain a compound of formula (I)wherein R^(C) is NHSO₂R^(S).

The peptide coupling to give compound I in Scheme VII could be performedusing any of the conventional peptide coupling reagents and protocolsknown in the art. Examples of suitable reagents and conditions areoutlined above with respect to peptide coupling step of Scheme V.

and when R^(C) is a C₁-C₆ alkoxy group, optionally subjecting thecompound of formula (I) to de-protection conditions to obtain a compoundof formula (I) wherein R^(C) is a hydroxyl group;and when R^(C) is a hydroxyl group in the resulting compound of formula(I), optionally coupling this compound with a sulfonamide of formulaR^(S)SO₂NH₂ in the presence of a suitable coupling agent, such ascarbodiimide reagents, TBTU or HATU, to obtain a compound of formula (I)wherein R^(C) is NHSO₂R^(S).

The peptide coupling to give compound I in Scheme VIII could beperformed using any of the conventional peptide coupling reagents andprotocols known in the art. Examples of suitable reagents and conditionsare outlined above with respect to peptide coupling step of Scheme V.

and when R^(C) is a C₁-C₆ alkoxy group, optionally subjecting thecompound of formula (I) to de-protection conditions to obtain a compoundof formula (I) wherein R^(C) is a hydroxyl group;and when R^(C) is a hydroxyl group in the resulting compound of formula(I), optionally coupling this compound with a sulfonamide of formulaR^(S)SO₂NH₂ in the presence of a suitable coupling agent, such ascarbodiimide reagents, TBTU or HATU, to obtain a compound of formula (I)wherein R^(C) is NHSO₂R^(S).

For the formation of compound I in Scheme IX, the S_(N)Ar reaction couldbe performed in any organic solvent, or organic solvent mixture, thatwill not react with the base used, such as DMSO, DMF, DMA, THF, NMP,DMPU, DME, and the like, or mixtures thereof, with DMSO, DMF and thecombination of DMF and THF being preferred. The reaction could beperformed at a temperature between −20° C. and 150° C. with 0° C. to 25°C. being preferred. Any base capable of forming the alkoxide could beused such as t-BuOK, LDA, KHMDS, KDMO, LiTMP, Cs-t-amylate and the like,with t-BuOK, Cs-t-amylate and KDMO being preferred, and KDMO being mostpreferred. The preferred amount of base used is 3-6 equivalents.Cosolvents such as alkanes and cycloalkanes could also be used, withheptane being a preferred co-solvent.

III.A. General Embodiments Relating to Schemes II, III, IV and IX

Another aspect of the present invention are the S_(N)Ar processesdepicted in Schemes II, III, IV and IX, and depicted generally as aprocess for preparing a compound of formula II:

wherein Het, R¹ and Alk are as defined for formula I above;

-   R^(A) is PG wherein PG is an amino-protecting group, or R^(A) is a    moiety of the formula:-   R^(B) is CO₂H or a moiety of the formula:    and wherein A, B and R², R³ and R^(C) are as defined for formula I    above;    said process comprising reacting a compound of formula QUIN, wherein    X is a halogen atom or SO₂R group, wherein R is C₁₋₆alkyl, C₆ or C₁₀    aryl or heteroaryl, with a compound of formula P2 to obtain a    compound of formula II:    wherein Alk, Het, R¹, R^(A) and R^(B) in formulas QUIN and P2 are    the same as defined above for formula II.

Another aspect of the present invention are the P2-QUIN and substitutedP2-QUIN compounds prepared by the S_(N)Ar processes depicted in SchemesII, III, IV and IX, and as depicted generally by formula II below:

wherein Het, R′ and Alk are as defined for formula I above;

-   R^(A) is H or PG wherein PG is an amino-protecting group, or R^(A)    is a moiety of the formula:-   R^(B) is CO₂H or a moiety of the formula:    and wherein A, B and R², R³ and R^(C) are as defined for formula I    above; and wherein when R^(A) is    then R^(B) cannot be

Additional embodiments of formula II above are:

-   (1) wherein R^(A) is H or PG and R^(B) is CO₂H; or-   (2) wherein R^(A) is a moiety of the formula:    and R^(B) is CO₂H; or-   (3) wherein R^(A) is H or PG and R^(B) is a moiety of the formula:    IV. Preparation of Peptidic Starting Materials

The mono-. di- and tripeptidic starting materials employed in the aboveschemes may be synthesized from known materials using the procedures asoutlines in the Schemes X to XIII below.

The peptide coupling to give P3-P2-Me in Scheme X could be performedusing any of the conventional peptide coupling reagents and protocolsknown in the art. Examples of suitable reagents and conditions areoutlined above with respect to peptide coupling step of Scheme V. Thepeptide coupling step to give P3-P2-Me in Scheme X is preferablyperformed in the presence of tosyl chloride and N-methylmorpholine inacetonitrile.

The subsequent hydrolysis to give P3-P2 in Scheme X could be performedwithout isolation of the P3-P2-Me intermediate using an aqueous basicsolution, optionally containing a co-solvent that is miscible with H₂Osuch as THF, dioxane, alcohols, MeCN, DME or combinations of theseco-solvents. The preferred solvent mixture would be aqueous basecontaining THF as a co-solvent. Any water soluble base could be usedsuch as LiOH, NaOH, KOH, Na₂CO₃, K₂CO₃, and the like. The preferred basewould be LiOH. The amount of base could vary from 1 to 100 equivalentswith 1-10 equivalents being preferred. The concentration of base couldrange from 0.25 M to 12 M, with 1-4 M being preferred. The reactiontemperature could vary from −40° C. to 100° C., with −20° C. to 50° C.being preferred.

The peptide coupling to give P2-P1-PG, wherein PG is an amino-protectinggroup, in Scheme XI could be performed using any of the conventionalpeptide coupling reagents and protocols known in the art. Examples ofsuitable reagents and conditions are outlined above with respect topeptide coupling step of Scheme V.

The removal of the amino-protecting group in the last step of Scheme XIcould be performed under the conditions as described above for thedeprotection step in Scheme IV.

The peptide couplings to give P3-P2-P1 in Scheme XII could be performedusing any of the conventional peptide coupling reagents and protocolsknown in the art. Examples of suitable reagents and conditions areoutlined above with respect to peptide coupling step of Scheme V. Whenthe R^(C) is an alkoxy group in the P1 moiety of the mono- or dipeptidicstarting materials, the resulting tripeptide compound P3-P2-P1 whereinR^(C) is an alkoxy group may then be subjected to standard hydrolysisconditions to obtain the corresponding tripeptide comound wherein R^(C)is hydroxyl. Examples of suitable hydrolysis conditions are as outlinedabove with respect to the hydrolysis step of Scheme X.

Additional embodiments of the invention are directed to the individualsteps of the multistep general synthetic method described above and theindividual intermediates used in these steps. These individual steps andintermediates of the present invention are described in detail below.All substituent groups are as defined in the general multi-step methodabove.

V. Preferred Embodiments of the Compound of Formula (I)

The compounds that may be prepared by the processes of the presentinvention are compounds of the formula (I) as previously set forth, i.e.compound of the following formula:

wherein Het is a five-, six- or seven-membered saturated or unsaturatedheterocycle containing from one to four heteroatoms selected fromnitrogen, oxygen and sulfur; said heterocycle being substituted with R¹at any available position on the heterocycle;

-   R¹ is R²⁰, —NR²²COR²⁰, —NR²²COOR²⁰—NR²²R²¹ and —NR²²CONR²¹R²³,    wherein-   R²⁰ is selected from (C₁₋₈)alkyl, (C₃₋₇)cycloalkyl and    (C₃₋₇)cycloalkyl(C₁₋₄)alkyl-, wherein said cycloalkyl or    cycloalkylalkyl may be mono-, di- or tri-substituted with    (C₁₋₃)alkyl;-   R²¹ is H or has one of the meanings of R²⁰ as defined above,-   R²² and R²³ are independently selected from H and methyl,-   Alk is a C₁-C₆ alkyl group;-   A is O or NH;-   B is (C₁₋₁₀)alkyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₄)alkyl,    -   a) wherein said cycloalkyl, cycloalkylalkyl may be mono-, di- or        tri-substituted with (C₁₋₃)alkyl; and    -   b) wherein said alkyl, cycloalkyl, cycloalkylalkyl may be mono-        or di-substituted with substituents selected from hydroxy and        (C₁₋₄)alkoxy; and    -   c) wherein all said alkyl-groups may be mono-, di- or        tri-substituted with halogen; and    -   d) wherein said cycloalkyl-groups being 4-, 5-, 6- or 7-membered        having optionally one (for the 4-, 5, 6, or 7-membered) or two        (for the 5-, 6- or 7-membered) —CH₂-groups not directly linked        to each other replaced by —O— such that the O-atom is linked to        the group A via at least two C-atoms;-   R² is (C₁₋₈)alkyl, (C₃₋₇)cycloalkyl or (C₃₋₇)cycloalkyl(C₁₋₃)alkyl,    wherein said cycloalkyl groups may be mono-, di- or tri-substituted    with (C₁₋₄)alkyl;-   R³ is ethyl or vinyl;-   R^(C) is hydroxyl, C₁-C₆ alkoxy or NHSO₂R^(S) wherein R^(S) is    (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl, (C₃₋₇)cycloalkyl(C₁₋₆)alkyl, phenyl,    naphthyl, pyridinyl, phenyl(C₁₋₄)alkyl, naphthyl(C₁₋₄)alkyl or    pyridinyl(C₁₋₄)alkyl; all of which optionally being mono-, di- or    tri-substituted with substituents selected from halogen, hydroxy,    cyano, (C₁₋₄)alkyl, (C₁₋₆)alkoxy, —CO—NH₂, —CO—NH(C₁₋₄-alkyl),    —CO—N(C₁₋₄-alkyl)₂, —NH₂, —NH(C₁₋₄-alkyl) and —N(C₁₋₄-alkyl)₂; and    all of which optionally being monosubstituted with nitro;    -   or R^(S) can be further selected from: —NH(C₁₋₆alkyl),        N(C₁₋₆alkyl)₂, -Het,        or a pharmaceutically acceptable salt or ester thereof.

In another embodiment of the compounds of formula (I):

-   Het is selected from the following groups, wherein the arrow    desigantes the position of the bond to the quinoline group of    formula (I), said heterocycle being substituted with the R¹ group at    any available position on the heterocycle:-   R¹ is R²⁰, —NHCORO²⁰, —NHCOOR²⁰, —NHR²¹ and —NHCONR²¹R²², wherein-   R²⁰ is selected from (C₁₋₈)alkyl, (C₃₋₇)cycloalkyl,    (C₁₋₃)alkyl-(C₃₋₇)cycloalkyl, wherein said cycloalkyl,    alkyl-cycloalkyl may be mono-, di- or tri-substituted with    (C₁₋₃)alkyl; and-   R²⁰ is H or has one of the meanings of R²⁰ as defined above; and-   R²² is H or methyl;-   Alk is a C₁₋₃alkyl group;-   A is O or NH;-   B is (C₂₋₈)alkyl, (C₃₋₇)cycloalkyl or C₁₋₃alkyl-C₃₋₇cycloalkyl, all    said groups being optionally mono- or di-substituted with methyl or    halogen;-   R² is (C₁₋₆)alkyl or (C₃₋₇)cycloalkyl, both of which being    optionally substituted by 1 to 3 substituents selected from C₁₋₄    alkyl;-   R³ is ethyl or vinyl; and-   R^(C) is hydroxy, NHSO₂-methyl, NHSO₂-ethyl, NHSO₂-(1-methyl)ethyl,    NHSO₂-propyl, NHSO₂-cyclopropyl, NHSO₂-cyclopropylmethyl,    NHSO₂-cyclobutyl, NHSO₂-cyclopentyl or NHSO₂-phenyl.

In yet another embodiment of formula (I):

-   Het is selected from the following groups, wherein the arrow    desigantes the position of the bond to the quinoline group of    formula (I), said heterocycle being substituted with the R¹ group at    any available position on the heterocycle:-   R¹ is —NHCOR²⁰, —NHCOOR²⁰ or —NHR²¹, wherein R²⁰ and R²¹ are    independently selected from: methyl, ethyl, n-propyl, i-propyl and    2,2-dimethylpropyl;-   Alk is a C₁₋₃alkyl group;-   A is O or NH;-   B is selected from: ethyl, n-propyl, cyclopentyl,-   R² is selected from 1,1-dimethylethyl, cyclopentyl, cyclohexyl and    1-methylcyclohexyl;-   R³ is vinyl; and R^(C) is hydroxy, NHSO₂-methyl, NHSO₂-cyclopropyl    and NHSO₂-phenyl.

In yet another embodiment of the compounds of formula (I):

-   Het-R¹ is a group of the formula    wherein the arrow desigantes the position of the bond to the    quinoline group of formula (I);-   R¹ is —NHCOR²⁰, wherein R²⁰ is selected from: methyl, ethyl,    n-propyl, i-propyl and 2,2-dimethylpropyl;-   Alk is a C₁₋₃alkyl group;-   A is O;-   B is selected from: ethyl, n-propyl, 2-fluoroethyl, and cyclopentyl;-   R² is selected from 1,1-dimethylethyl and cyclohexyl; R³ is vinyl;    and R^(C) is hydroxy.

Representative compounds of formula (I) that may be prepared by theprocesses described herein can be found in Llinas-Brunet et al., U.S.Patent Application Publication No. 2005/0020503 A1, which is hereinincorporated by reference in its entirety, including any specificcompounds in this publication falling within the scope of formula (I) ofthe present invention. Representative compounds that may be prepared bythe process of the present invention are also listed in the tablesbelow: TABLE 1

Cpd. B L⁰ L¹ R² 1001

MeO- Br-

1002

MeO- Br-

1003

MeO- Br-

1004

MeO- Br-

1005

MeO- Br

1006

MeO- Br

1007

MeO- Br

1008

MeO- Br

1009

MeO- Br

1010

MeO- Br

1011

MeO- Br

1012

MeO- Br

1013

MeO- Br

1014

MeO- Br

1015

MeO- Br

1016

MeO- Br

1017

MeO- Br

1018

MeO- Br

1019

MeO- Br

1020

MeO- Br

1021

MeO- Br

1022

MeO- Br

1023

MeO- Br

1024

MeO- Br

1025

MeO- Br

1026

MeO Br

1027

MeO Br

1028

EtO- Br

1029

EtO- Br

1030

EtO- Br

1031

EtO- Br

1032

PrO- Br

1033

PrO- Br

1034

PrO- Br

1035

PrO- Br

1036

MeO- Br

1037

MeO- Br

1038

MeO Br

1039

MeO- Br

1040

MeO- Br

1041

MeO- Br

1042

MeO Br

1043

MeO Br

1044

MeO- Br

1045

MeO Br

1046

MeO Br

1047

MeO Br

1048

MeO Br

1049

MeO Br

1050

MeO Br

1051

MeO Br

1052

MeO Br

1053

MeO Br

1054

MeO Br

TABLE 2

Cpd. B L⁰ L¹ R² 2001

MeO- Br-

1. A process for preparing a compound of formula II:

wherein Het is a five-, six- or seven-membered saturated or unsaturatedheterocycle containing from one to four heteroatoms selected fromnitrogen, oxygen and sulfur; said heterocycle being substituted with R¹at any available position on the heterocycle; R¹ is R²⁰, —NR²²COR²⁰,—NR²²COOR²⁰—NR²²R²¹ and —NR²²CONR²¹R²³, wherein R²⁰ is selected from(C₁₋₈)alkyl, (C₃₋₇)cycloalkyl and (C₃₋₇)cycloalkyl(C₁₋₄)alkyl-, whereinsaid cycloalkyl or cycloalkylalkyl may be mono-, di- or tri-substitutedwith (C₁₋₃)alkyl; R²¹ is H or has one of the meanings of R²⁰ as definedabove, R²² and R²³ are independently selected from H and methyl, Alk isa C₁-C₆ alkyl group; R^(A) is PG wherein PG is an amino-protectinggroup, or R^(A) is a moiety of the formula:

wherein: A is O or NH; B is (C₁₋₁₀)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₄)alkyl, a) wherein said cycloalkyl, cycloalkylalkylmay be mono-, di- or tri-substituted with (C₁₋₃)alkyl; and b) whereinsaid alkyl, cycloalkyl, cycloalkylalkyl may be mono- or di-substitutedwith substituents selected from hydroxy and (C₁₋₄)alkoxy; and c) whereinall said alkyl-groups may be mono-, di- or tri-substituted with halogen;and d) wherein said cycloalkyl-groups being 4-, 5-, 6- or 7-memberedhaving optionally one (for the 4-, 5, 6, or 7-membered) or two (for the5-, 6- or 7-membered)-CH₂-groups not directly linked to each otherreplaced by —O— such that the O-atom is linked to the group A via atleast two C-atoms; and R² is (C₁₋₈)alkyl, (C₃₋₇)cycloalkyl or(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, wherein said cycloalkyl groups may bemono-, di- or tri-substituted with (C₁₋₄)alkyl; R^(B) is CO₂H or amoiety of the formula:

wherein: R³ is ethyl or vinyl; and R^(C) is hydroxyl, C₁-C₆ alkoxy orNHSO₂R^(S) wherein R^(S) is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl, phenyl, naphthyl, pyridinyl,phenyl(C₁₋₄)alkyl, naphthyl(C₁₋₄)alkyl or pyridinyl(C₁₋₄)alkyl; all ofwhich optionally being mono-, di- or tri-substituted with substituentsselected from halogen, hydroxy, cyano, (C₁₋₄)alkyl, (C₁₋₆)alkoxy,—CO—NH₂, —CO—NH(C₁₋₄-alkyl), —CO—N(C₁₋₄-alkyl)₂, —NH₂, —NH(C₁₋₄-alkyl)and —N(C₁₋₄-alkyl)₂; and all of which optionally being monosubstitutedwith nitro; or R^(S) can be further selected from: —NH(C₁₋₆alkyl),N(C₁₋₆alkyl)₂, -Het,

said process comprising reacting a compound of formula QUIN, wherein Xis a halogen atom or SO₂R group, wherein R is C₁₋₆alkyl, C₆ or C₁₀ arylor heteroaryl, with a compound of formula P2 to obtain a compound offormula II:

wherein Alk, Het, R¹, R^(A) and R^(B) in formulas QUIN and P2 are thesame as defined above for formula II.
 2. A process according to claim 1,wherein R^(A) is PG and R^(B) is CO₂H.
 3. A process according to claim1, wherein R^(A) is a moiety of the formula:

and R^(B) is CO₂H.
 4. A process according to claim 1, wherein R^(A) isPG and R^(B) is a moiety of the formula:


5. A process according to claim 1, wherein R^(A) is a moiety of theformula:

and R^(B) is is a moiety of the formula:


6. A compound of formula II:

wherein Het is a five-, six- or seven-membered saturated or unsaturatedheterocycle containing from one to four heteroatoms selected fromnitrogen, oxygen and sulfur; said heterocycle being substituted with R¹at any available position on the heterocycle; R¹ is R²⁰, —NR²²COR²⁰,—NR²²COOR²⁰—NR²²R²¹ and —NR²²CONR²¹R²³, wherein R²⁰ is selected from(C₁₋₈)alkyl, (C₃₋₇)cycloalkyl and (C₃₋₇)cycloalkyl(C₁₋₄)alkyl-, whereinsaid cycloalkyl or cycloalkylalkyl may be mono-, di- or tri-substitutedwith (C₁₋₃)alkyl; R²¹ is H or has one of the meanings of R²⁰ as definedabove, R²² and R²³ are independently selected from H and methyl, Alk isa C₁-C₆ alkyl group; R^(A) is H or PG wherein PG is an amino-protectinggroup, or R^(A) is a moiety of the formula:

wherein: A is O or NH; B is (C₁₋₁₀)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₄)alkyl, a) wherein said cycloalkyl, cycloalkylalkylmay be mono-, di- or tri-substituted with (C₁₋₃)alkyl; and b) whereinsaid alkyl, cycloalkyl, cycloalkylalkyl may be mono- or di-substitutedwith substituents selected from hydroxy and (C₁₋₄)alkoxy; and c) whereinall said alkyl-groups may be mono-, di- or tri-substituted with halogen;and d) wherein said cycloalkyl-groups being 4-, 5-, 6- or 7-memberedhaving optionally one (for the 4-, 5, 6, or 7-membered) or two (for the5-, 6- or 7-membered)-CH₂-groups not directly linked to each otherreplaced by —O— such that the O-atom is linked to the group A via atleast two C-atoms; and R² is (C₁₋₈)alkyl, (C₃₋₇)cycloalkyl or(C₃₋₇)cycloalkyl(C₁₋₃)alkyl, wherein said cycloalkyl groups may bemono-, di- or tri-substituted with (C₁₋₄)alkyl; R^(B) is CO₂H or amoiety of the formula:

wherein: R³ is ethyl or vinyl; and R^(C) is hydroxyl, C₁-C₆ alkoxy orNHSO₂R^(S) wherein R^(S) is (C₁₋₆)alkyl, (C₃₋₇)cycloalkyl,(C₃₋₇)cycloalkyl(C₁₋₆)alkyl, phenyl, naphthyl, pyridinyl,phenyl(C₁₋₄)alkyl, naphthyl(C₁₋₄)alkyl or pyridinyl(C₁₋₄)alkyl; all ofwhich optionally being mono-, di- or tri-substituted with substituentsselected from halogen, hydroxy, cyano, (C₁₋₄)alkyl, (C₁₋₆)alkoxy,—CO—NH₂, —CO—NH(C₁₋₄-alkyl), —CO—N(C₁₋₄-alkyl)₂, —NH₂, —NH(C₁₋₄-alkyl)and —N(C₁₋₄-alkyl)₂; and all of which optionally being monosubstitutedwith nitro; or R^(S) can be further selected from: —NH(C₁₋₆alkyl),N(C₁₋₆alkyl)₂, -Het,

and wherein when R^(A) is

then R^(B) cannot be


7. A compound of formula II according to claim 6, wherein R^(A) is H orPG and R^(B) is CO₂H.
 8. A compound of formula II according to claim 6,wherein R^(A) is a moiety of the formula:

and R^(B) is CO₂H.
 9. A compound of formula II according to claim 6,wherein R^(A) is H or PG and R^(B) is a moiety of the formula:


10. A compound of the formula QUIN′:

wherein Het is a five-, six- or seven-membered saturated or unsaturatedheterocycle containing from one to four heteroatoms selected fromnitrogen, oxygen and sulfur; said heterocycle being substituted with R¹at any available position on the heterocycle; R¹ is R²⁰, —NR²²COR²⁰,—NR²²COOR²⁰—NR²²R²¹ and —NR²²CONR²¹R²³, wherein R²⁰ is selected from(C₁₋₈)alkyl, (C₃₋₇)cycloalkyl and (C₃₋₇)cycloalkyl(C₁₋₄)alkyl-, whereinsaid cycloalkyl or cycloalkylalkyl may be mono-, di- or tri-substitutedwith (C₁₋₃)alkyl; R²¹ is H or has one of the meanings of R²⁰ as definedabove, R²² and R²³ are independently selected from H and methyl, Alk isa C₁-C₆ alkyl group; and X′ is a hydroxyl group, a halogen atom or anSO₂R group, wherein R is C₁₋₆alkyl, C₆ or C₁₀ aryl or heteroaryl.
 11. Acompound of formula QUIN′ according to claim 10, wherein X′ is ahydroxyl group.
 12. A compound of formula QUIN′ according to claim 10,wherein X′ is a halogen atom.
 13. A compound of formula QUIN′ accordingto claim 10, wherein X′ is an SO₂R group wherein R is C₁₋₆alkyl, C₆ orC₁₀ aryl or heteroaryl.
 14. A process for preparing a compound offormula QUIN′ according to claim 10, said process comprising: (a) whenX′ is a hydroxyl group, cyclizing a compound of formula 6 in thepresence of a sutiable base in a suitable solvent to obtain a compoundof formula 7:

or (b) when X′ is a halogen atom, treating a compound of formula 7 witha halogenating agent to obtain a compound of formula QUIN-1:

or (c) when X′ is an SO₂R group, R is C₁₋₆alkyl, C₆ or C₁₀ aryl orheteroaryl, either: (1) treating a compound of formula 7 with ahalogenating agent to obtain a compound of formula QUIN-1 and thenreacting compound QUIN-1 with a sulfinate salt RSO₂M, where R is asdefined previously and M is an alkali metal, to obtain a compound offormula QUIN-2; or (2) reacting a compound of formula 7 with a compoundR_(A)SO₂Cl wherein R_(A) is an electron rich arene group, in thepresence of a suitable base, and then reacting the resulting compound insitu, under acidic conditions, with a sulfinate salt RSO₂M, where R isas defined previously, wherein M is an alkali metal, to obtain acompound of formula QUIN-2:

wherein Het, R¹ and Alk are as defined in claim
 10. 15. A compound offormula 4 or formula 6:

wherein Het is a five-, six- or seven-membered saturated or unsaturatedheterocycle containing from one to four heteroatoms selected fromnitrogen, oxygen and sulfur; said heterocycle being substituted with R¹at any available position on the heterocycle; R¹ is R²⁰, —NR²² COR²⁰,—NR²²COOR²⁰—NR²²R²¹ and —NR²²CONR²¹R²³, wherein R²⁰ is selected from(C₁₋₈)alkyl, (C₃₋₇)cycloalkyl and (C₃₋₇)cycloalkyl(C₁₋₄)alkyl-, whereinsaid cycloalkyl or cycloalkylalkyl may be mono-, di- or tri-substitutedwith (C₁₋₃)alkyl; R²¹ is H or has one of the meanings of R²⁰ as definedabove, R²² and R²³ are independently selected from H and methyl, eachAlk is independently a C₁-C₆ alkyl group; and X is a hydroxyl group, ahalogen atom or an SO₂R group, wherein R is C₁₋₆alkyl, C₆ or C₁₀ aryl orheteroaryl.